The overarching goal of this application is to decipher novel mechanisms utilized by human placental trophoblasts to resist viral infections and to communicate antiviral signals locally and systemically. Hematogenous spread of microbes from the maternal host to the placenta can have devastating consequences to the developing embryo. Moreover, even in the absence of vertical transmission, viral pathogens that compromise maternal health may jeopardize pregnancy outcome. Located in direct contact with maternal blood, the placental trophoblasts constitute the cardinal feto-placental barrier, and are capable of interfacing with the maternal local and systemic environments, including components of the maternal immune system and cellular barriers such as the microvascular endothelium. The proposed research represents the synergistic interaction of expertise in virology and placental biology, resulting in a transdisciplinary pursuit that integrates the function of trophoblast-specific microRNAs with distinctive cellular pathways that suppress viral replication. Our preliminary data indicate that primary human trophoblasts are highly resistant to infection by a wide range of unrelated viruses, and that non-trophoblastic cells can be endowed with this resistance by targeted expression of primary trophoblasts-derived microRNAs. We plan to identify the specific microRNAs that mediate this effect, and define mechanisms of microRNA transport to non-trophoblastic target cells, where they stimulate autophagy as a means to attenuate viral replication. We will analyze the role of trophoblastic microRNAs in the regulation of autophagy, and examine the pathways that may allow certain viruses to evade this line of cellular defense. Thus, our grant proposal goes beyond investigation of the mechanisms of virus-induced injury, and instead identifies exciting new molecular pathways that may transfer innate and adaptive responses to virus infection. Together, we identified a novel pathway for transmissible placental resistance to viral pathogens. In deciphering the underlying mechanisms that constitute this pathway we may not only illuminate the basis of trophoblast resistance to pathogens, but also inform the development of innovative therapeutics designed to mitigate and/or prevent viral infections, thus reducing the burden of infection related feto-maternal morbidity and mortality. PUBLIC HEALTH RELEVANCE: Infections by viral pathogens during pregnancy are a significant source of maternal morbidity, and can have devastating developmental consequences to the embryo, including pregnancy loss. We have uncovered an extraordinary placental defense mechanism to suppress viral infections of placental and non-placental cells, which may play a pivotal role in developing strategies for mitigating pathogen-mediated placental infection and feto-maternal disease.